1. Technical Field of the Invention
The invention relates to a process for the preparation of (5-[[.omega.-(dialkylamino)alkyl]amino]-8-hydroxyimidazo[4,5,1-de]acridin- 6-ones of general formula (I), ##STR3##
wherein R.sup.1 and R.sup.2 represent alkyl groups of 1 to 4 carbon atoms which may be the same or different and n is 2 to 5.
These compounds show anti-neoplastic activity, in particular against leukaemia, melanomas or colon adenocarcinomas, as more fully set forth in Z. Mazerska et al., Anti-Cancer Drug Design 11, 73-88 (1996).
The invention further relates to certain new 1-[[.omega.-(dialkylamino)alkyl]amino]-4-substituted-7-hydroxyacridin-9(10 H)-ones, useful as intermediates in the process of the invention and also having anti-neoplastic activity.
2. Description of the Related Art
Methods of preparation of the imidazoacridinones of general formula I are known from PCT Application WO-A-92/15583 and W. Cholody et al. J. Med. Chem 35, 378-382 (1992), and depend on cyclisation of amines of general formula (II). The amines (II) can be prepared by a multi step process, as described in the above patent application and shown in Scheme 1: ##STR4##
It was a problem that the 7-hydroxy-4-amino-1-[[.omega.-(dialkylamino)alkyl]amino]acridin-9(10H)-one compounds of formula II are unstable. See particularly W. Cholody et al. J. Med. Chem. 35, 378-382 (1992), at page 379, right-hand column. This problem might be overcome by running the reduction and cyclisation as a single step in a "one pot reaction", by heating the nitro compounds of formula III with Raney nickel and formic acid. This reaction was carried out in the context of synthesising some imidazo[4,5,1-de][1,4]-diazepino[5,6,7-mn]acridines, see W. Cholody et al., J. Heterocyclic Chem. 29, 1749-1752 (1992). This procedure does not require isolation of the unstable amine (II). Unfortunately, however, another problem arose. The purification of the preferred compound 5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo[4,5,1-de]acridin-6-one, of formula I, wherein R.sup.1 and R.sup.2 are ethyl and n is 2, free of nickel ions is difficult because both the compound and nickel ions are soluble in acidic solution, but precipitated by adding alkali. This is a serious problem, expected to arise to a greater or less degree with all the compounds of formula I, especially as they are intended for pharmaceutical use.
When, to avoid contamination by nickel ions, the reduction-cyclisation mixture composed of Raney nickel and formic acid was replaced by formic acid and palladium, the product compounds of formula (I) decomposed slowly during the reaction.